Functionalized nanomaterials

ABSTRACT

A functionalized nanomaterial, such as a nanoparticle, can include a polythioaminal functionalized surface. The polythioaminal linked to the surface of the nanomaterial can be bonded to a compound such as therapeutic and/or diagnostic materials. The thiol-based linkages can be used to bond the polythioaminal to both the nanomaterial and the therapeutic and/or diagnostic materials. Polythioaminals can be prepared via reactions of triazine and dithiols. Polythioaminals thus prepared can be further modified to provide linkages to the nanomaterial and other compounds such as medicinal compound, peptides, and dyes. Nanomaterials including such compounds linked thereto via the polythioaminal can be supplied for therapeutic and/or diagnostic purposes to biological target regions.

BACKGROUND

The present disclosure relates to functionalized nanomaterials, and morespecifically, to nanoparticles functionalized with polythioaminals.

SUMMARY

According to one embodiment of the present disclosure, a materialincludes a nanomaterial and a polythioaminal having a structure:

wherein each R¹ is independently an organic or hetero-organic species,each R² is independently a substituent having a molecular weight no morethan about 120 Daltons, X is a sulfur bonded species, Z is a linkage tothe nanomaterial, and n is an integer greater than or equal to 1. Insome examples, X comprises a theranostic compound such as a dyemolecule, a biologically active species, or a therapeutic agent, such asa medicinal compound or the like. The nanomaterial can be ananoparticle. In some embodiments, at least one instance of R¹ caninclude a polyethylene glycol. In general, Z can be anything which linksthe polythioaminal to the surface of the nanomaterial, inclusive of adirect covalent bond to the surface. Z may include at least one carbonatom. In some examples, R² is a methyl group.

According to another embodiment of the present disclosure, a methodcomprises functionalizing a nanomaterial to provide a thiol end groupconnected thereto. The functionalized nanomaterial is then exposed to apolythioaminal such that the polythioaminal becomes linked tonanomaterial via the thiol end group. The polythioaminal exposed to thefunctionalized nanomaterial has a general structure:

wherein each R¹ is independently an organic or hetero-organic species,each R² is independently a substituent having a molecular weight no morethan about 120 Daltons, and n is an integer greater than or equal to 1.In some embodiments, the method can further comprise exposing thenanomaterial that has the polythioaminal linked thereto to a thiolcompound have a general structure HS—X, wherein X is a species includingat least one carbon. Species X in some examples can include at least oneof an alkyl group, an aromatic group, a peptide, or a nucleotide.Species can X includes a theranostic compound, which in this contextrefers to compound that has at least one of therapeutic or diagnosticeffect. In some embodiments, the nanomaterial can be functionalized byexposing the nanomaterial to a dithiol.

In still another embodiment, a method comprises supplying a nanomaterialto a target region of a biological sample. The nanomaterial has atheranostic compound linked thereto via a polythioaminal having astructure:

wherein each R¹ is independently an organic or hetero-organic species,each R² is independently a substituent having a molecular weight no morethan about 120 Daltons, X is the theranostic compound or a linkagethereto, Z is a linkage to the nanomaterial, and n is an integer greaterthan or equal to 1. In some embodiments, the nanomaterial is a goldnanoparticle.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a nanomaterial functionalized with polythioaminal.

FIG. 2 depicts a process for functionalizing a nanoparticle withpolythioaminal.

FIG. 3 depicts a polythioaminal-functionalized nanomaterial loaded witha diagnostic and/or therapeutic compound.

FIG. 4 depicts a process for loading a polythioaminal-functionalizednanoparticle with a diagnostic and/or therapeutic compound.

FIG. 5 depicts a process of using a diagnostic and/or therapeuticcompound loaded polythioaminal-functionalized nanoparticle.

DETAILED DESCRIPTION

FIG. 1 depicts a nanomaterial 110 functionalized with a polythioaminal.Nanomaterial 110 is, for example, a metal material such as gold.Nanomaterial 110 is, for example, a nanoparticle. Nanomaterial 110 has asurface coating 120. A polythioaminal 130 is covalently bonded tosurface coating 120. Surface coating 120 is formed, for example, bycontacting nanomaterial 110 with a dilute solution of a dithiol. Adithiol has the general structure (1):

HS—R′—SH  (1),

wherein R¹ includes at least one carbon. R can be an alkyl group, forexample, having 1 to 12 carbon atoms (C₁ to C₁₂), such as a hexylradical. Surface coating 120 can be formed using, for example, alkanedithiols such as butane dithiol, pentane dithiol, and hexane dithiol,any of which may be used as precursors. Aromatic dithiols such asbenzene dithiol, toluene dithiol, and xylene dithiol may also be used asprecursors to surface coating 120. The dithiol used in forming surfacecoating 120 may itself be a polymer species, such as a dithiol-cappedpolyolefin. Dithio-polyol species, such as dithio-alkane diols, triols,and the like, may also be used in forming surface coating 120.

As noted, nanomaterial 110 can be a nanoparticle. Nanoparticles havebeen generated with a variety of properties and compositions.Nanoparticles can be composed of materials such as metals,semiconductors, and dielectrics. For example, silicon, cadmium, lead,gadolinium, and gold can be formed into nanoparticles of variousdimensions. Gold is particularly useful in many instances because it isgenerally non-toxic in biological applications.

The outer surface of nanoparticles can be covered with various coatingsthat serve to minimize interactions between the nanoparticle and itssurroundings or otherwise alter properties of the nanoparticle. Forexample, polymers with at least one thiol end group can be bound to agold surface. Coatings on nanoparticles can also be utilized to providefor the attachment and delivery of therapeutic or diagnostic agents. Forexample, medicinal compounds and dyes can be attached to the coatednanoparticle by various means. In some instances, supramolecularcomplexes can be used to provide a route for the attachment andsubsequent delivery or release of therapeutic and diagnostic compounds.That is, for example, a medicinal compound or a dye compound can belinked to coated nanoparticles by supramolecular attachments(electrostatic forces, hydrogen bonding, or intermolecular forces) whichmay later be weakened or counteracted by changes in environmentalconditions of the nanoparticle (changes in solvent conditions, pHvariations, temperature increases, etc.). Reliance on supramolecularattachments in this context risks such things as premature or unintendedrelease of the medicinal or dye compounds outside of the intended targetarea because the attachment is relatively weak and thus potentiallyresponsive to small changes in environmental conditions. Furthermore,supramolecular attachments are subject to stochastic variations inattachment strength, thus continuous random fluctuations betweenmolecules may result in unintended release. Furthermore, the availablerelease/trigger mechanisms for these compounds may be difficult orimpossible to tailor as required for many intended applications.

In some instances, it may be preferred to covalently bond thetherapeutic and/or diagnostic compounds to the coated nanoparticle.However, compounds that have been covalently bound to nanoparticles maylater be difficult detach from the coated nanoparticle becausedetachment requires breaking of a covalent bond. Simple changes in localsolvent conditions, pH changes, or small increases in temperature willgenerally be insufficient to break a covalent bond. Additionally, makingthe initial covalent attachment may require many synthetic andpurifications steps and/or significant structural modification of thecompound being attached. Thus, the provision of therapeutic and/ordiagnostic compounds which are covalently attached to a nanoparticle yethave reliable release/trigger mechanisms with respect to changes inenvironmental conditions is desirable.

Therapeutic compounds can be, for example, medicinal compounds orbioactive materials intended to treat or ameliorate diseases, medicalconditions, or the like. Diagnostic compounds can be, for example,fluorescent dyes, imaging markers, or the like. Collectively,therapeutic compounds and diagnostic compounds may be referred to as“theranostic agents” or “theranostic compounds.” In an example, a dyemolecule and a medicinal compound could be loaded onto a coatednanoparticle such that both the dye and the medicinal compound releasefrom the nanoparticle in response to the same stimulus. The dye could beused to visualize and/or image the release point and the medicinalcompound could treat diseased cells proximate to the release point. Inanother example, the dye and the medicinal compound could be loaded ontothe coated nanoparticle such that the dye and the medicinal compoundrelease in response to different stimuli.

In FIG. 1, surface coating 120 is depicted as a continuous film orlayer, however this is for purposes of explanation, and surface coating120 may consist of discrete molecules (see e.g., FIG. 2). Furthermore,it is not required that surface coating 120 cover the entire surface ofnanomaterial 110 and in various embodiments it would be sufficient forsurface coating 120 to cover only some portion of nanomaterial 110. Ingeneral, formation of surface coating 120 is intended to promote thelater linkage of polythioaminal 130 to the nanomaterial 110. As such,any coating or material which allows polythioaminal 130 to bebonded/linked to nanomaterial 110 can be used for surface coating 120.In some examples, it may be unnecessary to separately provide surfacecoating 120 and polythioaminal 130 can be modified or designed toinclude an end group which bonds directly to the surface of nanomaterial110 in a desired manner. A polythioaminal thus designed or modified canform an equivalent to the surface coating 120 in the functionalizednanomaterial without requiring a separate step of preparing the surfaceof nanomaterial 110.

A process for preparing a polythioaminal functionalized nanoparticle isdepicted in FIG. 2. A nanoparticle 210 corresponds to nanomaterial 110in this instance. The composition of nanoparticle 210 is not aparticular limitation, but here, as an example, nanoparticle 210comprises gold. Other metals can be used in nanoparticle 210 such as,without limitation: gadolinium (Gd), cadmium (Cd), and lead (Pb). Thus,in some embodiments, nanoparticle 210 can be a gold nanoparticle, agadolinium nanoparticle, a cadmium nanoparticle, or a lead nanoparticle.In some applications, gold may be preferred as a generally bio-inactivematerial. In some applications, gadolinium may be useful material forvarious imaging processes.

In an initial process, nanoparticle 210 is exposed to dithiol 220. Agold surface of nanoparticle 210 reacts with one of the thiol end groupsto form a linkage between nanoparticle 210 and the remaining portion ofthe dithiol 220 molecule. Generally, steric hindrance will prevent boththiol end groups of a single dithiol 220 molecule from attaching to onenanoparticle 210. Similarly, in this context, it may be useful fordithiol 220 to be a relatively low molecular weight compound such asbutane dithiol, pentane dithiol, and hexane dithiol. Dilute reactantconditions are also typically used to prevent or at least limitagglomeration of nanoparticles and/or chemical linkage betweennanoparticles.

Linkage of dithiol 220 to nanoparticle 210 produces surface coatednanoparticle 230. The attached dithiol 220 molecules on surface coatednanoparticle 230 collectively correspond in this instance to surfacecoating 120 on nanomaterial 110, which may be discontinuous as describedabove. Dithiol 220 has the general structure (1) described above.

As depicted in FIG. 2, after surface coated nanoparticle 230 is formed,it is exposed to polythioaminal 240. The polythioaminal 240 has thegeneral structure (2):

In this general structure (2), each instance of R¹ is independently anorganic or hetero-organic group. In some cases, each instance of R¹ maybe the same species. Each instance of R² is independently an organic orhetero-organic group that may have a molecular weight of not more thanabout 120 Daltons, and each instance of R² may be the same species. Ineach instance, R¹ may be a hydrocarbon species, an aromatic and/oraliphatic; a polymer species such as polyethylene glycol, polyolspecies; or polyether species, any of which may have substituents. Inone embodiment, at least one instance of R¹ is polyethylene glycol. Inanother embodiment, each instance of R¹ is the same species.

Polythioaminal 240 can be prepared with the following polymerizationreaction scheme (3):

In reaction (3), an N-substituted hexahydrotriazine (HT) is reacted witha dithiol, or a mixture of dithiols, to form a polythioaminal 240, withR¹ and R² as described above. In general, a low molecular weightsubstituent (e.g., MW≦120 Daltons) is used for R² to provide highermolecular weight (M_(w)) polymers. However, R² could be a highermolecular weight substituent (e.g., MW>120 Daltons), but this wouldtypically result in lower molecular weight (M_(w)) polymers. Thereaction may be performed in a solvent medium such as N-methylpyrrolidone (NMP), or other suitable solvent, to control viscosity. Eachinstance of R² may be any group resulting in a byproduct (R²—NH₂) in thereaction scheme (3) which is volatile at a temperature below about 200°C., under vacuum if necessary. In general, if the generated byproductincorporating the R² group can be removed from the reaction mixture,polymer growth will be enhanced. For example, each instance of R² mayindependently be hydrogen, fluorine, methyl, or an alkyl group such asethyl, propyl, butyl, hexyl, or cyclohexyl.

For the dithiol in reaction (3), alkane dithiols such as butane dithiol,pentane dithiol, and hexane dithiol may be used. Aromatic dithiols suchas benzene dithiol, toluene dithiol, and xylene dithiol may also beused. The dithiol may be a polymer species, such as a dithiol-cappedpolyolefin. Dithio-polyol species may also be used, such asdithio-alkane diols, triols, and the like.

An example reaction for formation of polythioaminal 240 according toreaction scheme (3) is the reaction between1,3,5-trimethylhexahydrotriazine and 1,6-hexanedithiol, as follows inreaction (4):

Reaction (4) may be performed using NMP as solvent, or using thereactants alone as solvent. For example, the reaction (4) may beperformed in excess triazine up to about 2 equivalents, such as from 1.3to 1.5 equivalents, for example about 1.3 equivalents. The precursorsmay be obtained from commercial suppliers or may be synthesized.

Reaction (3) and reaction (4) may be performed according to thefollowing exemplary processing. In a stirred vessel, the dithiolprecursor is added to 1.3 equivalents of the HT precursor. The vessel ispurged with nitrogen or other inert gas and sealed, and the reactionmixture is heated to 85° C. The reaction mixture is maintained at 85° C.for 18 hours to form oligomers. Vacuum is then applied to the vessel toremove volatile byproducts, driving growth in molecular weight of theresulting polymer molecules according to LeChatelier's Principle. Thereaction is allowed to proceed for 24 hours, during which stirring maycease due to viscosity of the mixture. The resulting polymer istypically optically transparent and may range from a solid to a viscousliquid.

A method of forming a polythioaminal includes mixing an N-substitutedhexahydrotriazine and a dithiol in a vessel to form a first mixture, andheating the first mixture to form a polythioaminal polymer. Thesubstituent bonded to a nitrogen atom of the N-substitutedhexahydrotriazine is incorporated into an amine byproduct duringpolymerization. The substituent may be selected such that the ultimatebyproduct is volatile at temperatures up to about 200° C. so that thebyproduct can be removed during polymerization to increase molecularweight of the resultant polymer. The byproduct can be removed by pumpingoff the generated vapor and/or by inclusion of molecules or materialswhich remove or otherwise sequester the byproduct from the remainingreactants. The method may further comprise adding a thiol-reactivematerial to the polythioaminal polymer to form a second mixture, and thesecond mixture may be heated to form an end-modified polythioaminalpolymer, which may be, or include, a theranostic agent. A solvent may beadded to the N-substituted hexahydrotriazine or the dithiol prior toforming the first mixture, may be added during forming the firstmixture, may be added to the first mixture after forming the firstmixture, or may be added to the second mixture after forming the secondmixture. The end-modified polythioaminal polymer may be formed linked toa nanoparticle or nanomaterial or may be subsequently attached to ananoparticle or nanomaterial.

A higher reaction temperature for the formation of a polythioaminal maybe used in some cases to promote removal of byproducts during thereaction. One or more of the substituents bound to the nitrogen atoms ofthe hexahydrotriazine precursor will form a byproduct during thepolymerization reaction, so the substituent is generally chosen suchthat a byproduct incorporating a R² group from the N-substitutedhexahydrotriazine is volatile at temperatures below 200° C. Thisbyproduct will typically be a bis-amine that breaks down further to anamine. The byproduct may volatilize from heating alone, or vacuum may beapplied to encourage volatility. For at least this reason, highertemperatures may promote development of higher molecular weight in thepolymer through removal of byproducts. Alternatively, the byproducts canbe removed or otherwise sequestered from remaining reactants byinclusion of a “scavenger” type molecule that reacts with (or otherwiseremoves) the byproducts.

Formation of the polythioaminal polymer may be controlled by adjustingtemperature of the reaction mixture and solvent content. Solvents suchas N-methyl-2-pyrrollidone or other suitable aprotic solvents, which mayinclude dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA), propylene carbonate (PC), and propyleneglycol methyl ether acetate (PGMEA), of which any mixture may also beused. Application of heat and vacuum increases the resultantpolythioaminal molecular weight (weight-average or number average) up toa point. Because the polymer itself begins to decompose at temperaturesabove about 200° C., additional heating beyond this level may becounter-productive. In one aspect, polymerization is enhanced usinghexahydrotriazine N-substituents (R²) having a molecular weight lessthan about 120 Daltons. In another aspect, polymerization is enhancedusing hexahydrotriazine N-substituents (R²) which provide byproductshaving a room temperature vapor pressure of at least 10 Torr.Polythioaminals formed according to scheme (3) may, in some embodiments,have a weight-average molecular weight (M_(w)) from 3,800 Daltons to36,000 Daltons or at least a weight-average molecular weight (M_(w)) of10,000 Daltons.

As depicted in reaction (3) and reaction (4), the dithiol is a singletype of compound, but it is also possible to use a mixture of dithiolsin these reactions. A plurality of different dithiol precursors may beused to make a copolymer, terpolymer, or higher degree of mixed polymer.The polythiolaminal 240 may thus be a mixed polymer, such as a copolymerhaving the general formula (5):

where each instance of R³ is independently an organic or hetero-organicgroup different from R¹, and each instance of R³ may be the samespecies. As above in structure (2), each instance of R¹ is independentlyan organic or hetero-organic group, each instance of R¹ may be the samespecies, each instance of R² is independently an organic orhetero-organic group that may have a molecular weight of not more thanabout 120 Daltons, each instance of R² may be the same species, and mand n are each integers greater than or equal to 1. By sequencing andcontrolling availability of different dithiol precursors, mixed polymer(5) may be a prepared as a block copolymer.

It should also be noted that more than one HT precursor may be used tomake a polymer according to reaction (3). A random copolymer may be madeby simultaneously using two different triazine precursors with onedithiol precursor. A block copolymer may be made by making a firstsegment using a first triazine precursor, making a second segment usinga second triazine precursor, and then joining the first and secondsegments using the first triazine precursor, the second triazineprecursor, or a mixture of the first and second triazine precursors. Andas noted, various mixed polymers may be made by using mixtures ofdithiol precursors.

Polythioaminals of structure (2) and structure (5) have thiol endgroups. These thiol end groups are reactive, and polythioaminals ofstructure (2) and structure (5) may be further modified according to thefollowing general scheme (6):

In general, X and Z may be any thiol reactive species. Of particularuse, at least one of X or Z may be a therapeutic agent for treating amedical condition. X and/or Z may be a species selected from the groupconsisting of hydrogen, an alkane thiol, an aromatic thiol such as athiophenol or a thioaniline, a peptide, a protein, a thio-acid, anucleotide, and combinations thereof, with the proviso that X and Z arenot both hydrogen. X and/or Z may be a reactive or non-reactive species,a cargo, a linking group, a medicinal compound, a functional species forfurther modification after initial synthesis of the product polymer ofscheme (6), a polymerization starter, a chemical species capable ofinitiating depolymerization, or a combination of any of the foregoing.Any of the above species may be a linking species (or group) or anon-linking species (or group).

The reaction of HS—X and HS—Z with the polythioaminal of structure (2)or (5) may occur simultaneously or may be performed in sequence witheither component being provided first or second. In some instances,polythioaminal compounds with two X (or Z) end groups rather than one ofeach of X and Z may result. In a particular embodiment, the HS—Zcompound can be the surface coated nanoparticle 230 and polythioaminal240 can have the structure (2) or (5). The reaction between the thiolend groups of surface coated nanoparticle 230 and polythioaminal 240provides a polythioaminal functionalized nanoparticle 250. Whilepolythioaminal functionalized nanoparticle 250 is depicted having eachavailable end of the attached dithiol 220 molecules linked to apolythioaminal 240, such is not required. Unreacted ends of dithiol mayremain depending on amounts of polythioaminal 240 available forreaction, steric effects for already linked polythioaminal 240molecules, and the like. Likewise the actual number and specificarrangement of available thiol end groups on the depicted nanoparticlein FIG. 2 is not necessarily reflective of the number and arrangement inan actual material. Similarly, the depiction in FIG. 2 regardingrelative sizes of the various elements does not necessarily correspondto actual size relations between these elements.

With regard to FIG. 3, a nanomaterial is depicted as having theranosticcompounds loaded thereon. The theranostic loaded nanomaterial 300 issubstantially similar to the polythioaminal functionalized nanomaterial100 described above, except for the addition of theranostic compounds340 and 350. Theranostic compounds 340 and 350 are linked to thepolythioaminal 130. Theranostic compound 340 is, for example, amedicinal compound or other therapeutic agent intended to treat amedical condition. Theranostic compound 350 is, for example, afluorescent dye or other marker compound intended to aid diagnosis of amedical condition or the like. Though theranostic loaded nanomaterial300 is depicted as including both theranostic compounds 340 and 350, itis not required to attach different theranostic compounds to eachtheranostic loaded nanomaterial 300. That is, the nanomaterial may beloaded with only therapeutic compounds (e.g., 340) or only diagnosticcompounds (e.g., 350). Similarly, the number of theranostic compoundtypes is not limited to two and any number of different types oftheranostic compounds may be included when synthetically feasible.

FIG. 4 depicts a process for preparing a theranostic loaded nanomaterial300. A polythioaminal functionalized nanoparticle 250 is depicted. Aparticular polythioaminal portion is depicted in detail. Thepolythioaminal portion depicted corresponds in general to thepolythioaminal 240 used in preparing polythioaminal functionalizednanoparticle 250 according to the process of FIG. 2. Otherpolythioaminal portions present in the polythioaminal functionalizednanoparticle 250 are not depicted in detail for sake of clarity. Thepolythioaminal functionalized nanoparticle 250 is exposed to a compoundHS—X. Here in this example, X is a theranostic compound. The availablethiol end of the polythioaminal portion of nanoparticle 250 reacts withHS—X in a manner similar to scheme (6) such that theranostic compound Xis linked to the nanoparticle 250 to thereby provide theranostic loadednanomaterial 300.

Alternatively, X need not itself be a theranostic compound or otherwiseactive compound, but rather X can be a linking group such that eitherupon initial reaction or by subsequent processing, the followingstructure may result:

where K is any species bondable to X, and R¹, R², and n are defined asabove. Z may be a linkage to a nanoparticle. The linkage to thenanoparticle in some examples may be direct bonding to the surface ofthe nanoparticle when the nanoparticle has a thiol-reactive surface suchas a gold surface. K may be another polythioaminal segment that links toX via thiol reactivity, such as X is linked to a polythioaminalaccording to scheme (6), or K may be any other desired species, forexample another polymer, peptide, reactive or non-reactive species,cargo, linking group, functional species, polymerization starter, ordepolymerization starter that links to X via any suitable linkage. K mayalso be a species selected from the group consisting of hydrogen, analkane thiol, an aromatic thiol such as a thiophenol or a thioaniline, apeptide, a protein, a thio-acid, a nucleotide, and combinations thereof.

A nucleotide useable as the sulfur-bonded group X may be a thiolmodified oligonucleotide, as in either of the following:

Other species of interest for forming the sulfur-bonded groups Xinclude: dimercaptosuccinic acid

tiopronin

and the protein known as RANTES or chemokine ligand 5.

Polymer properties may be tuned by selecting the R¹ and R² groups. Inparticular, interaction of the polymer with water may be tuned byproviding various hydrophilic and/or hydrophobic substituents. By usinga large hydrophilic dithiol and a small hydrophobic substituted HT, awater-soluble polythioaminal may be made. For example, a polythioaminal240 prepared according to scheme (3) using a polyethylene glycol dithioland 1,3,5-trimethylhexahydrotriazine as reactants can be water soluble.Slow degradation of such a polymer into non-toxic components providesthe potential for therapeutic delivery agents that do not havesubstantial toxic effects.

In one example, the thiol-containing amphiphilic alpha-helical peptideCLLKKLLKKC-NH₂ was attached to a water-soluble polythioaminal polymer bymixing the peptide and polymer under mild heating. Initially, thepeptide was observed to form a white powder phase in the viscouspolymer. Maintaining the reaction mixture at 85° C. for 8 hours produceda single phase polymer-peptide product.

A method of forming a material includes mixing an N-substitutedhexahydrotriazine and a dithiol in a vessel to form a first mixture, andheating the first mixture to form a polythioaminal polymer. Some of thesubstituents bonded to nitrogen atoms in the N-substitutedhexahydrotriazine are ultimately incorporated into an amine byproductduring the polymerization reaction. These substituents should thusgenerally be selected such that the byproduct is volatile attemperatures up to about 200° C. so that the generated byproduct can beremoved from the polymerization reaction mixture and thereby to increasemolecular weight of the final polymer by driving the polymerizationreaction forward.

The method may further comprise adding a thiol-reactive material to thepolythioaminal polymer to form a second mixture, and the second mixturemay be heated to form an end-modified polythioaminal polymer, which maybe a therapeutic agent. A solvent may be added to the N-substitutedhexahydrotriazine or the dithiol prior to forming the first mixture, maybe added during forming the first mixture, may be added to the firstmixture after forming the first mixture, or may be added to the secondmixture after forming the second mixture. The end-modifiedpolythioaminal polymer may be formed linked to a nanoparticle ornanomaterial or may be subsequently attached to a nanoparticle ornanomaterial.

FIG. 5 depicts a method of using a theranostic loaded particle. Inmethod 500, a theranositc loaded particle is obtained in element 510 ofthe method. The theranostic loaded particle thus obtained may be, forexample, a theranostic loaded nanomaterial 300, which in this instancemay be a nanoparticle. The theranostic compounds loaded on the particlemay include a dye molecule and/or a therapeutic compound. Theranosticloaded nanoparticle is supplied to a target region in element 520 of themethod. The target region can be, for example, a portion of a body,tissue, organs, a living cell, or the like, either in vivo or in anextracted sample. The theranostic loaded particle can be supplied to thetarget region in a controlled manner such as localized injection or thelike or may be supplied in a more generalized manner to a region or bodyincluding the target region within. The linkage between the nanoparticleand the theranostic load can be reversible and/or degradable. Forexample, the linkage can be water soluble, temperature sensitive,chemically sensitive, pH sensitive, or otherwise altered byenvironmental stimulus. When the linkage is temperature sensitive,linkage between the theranostic load and the nanoparticle may be brokenor reversed by localized heating. Localized heating can be achieved by,for example, exposure of the nanoparticle to microwave or otherradiation. In some embodiments, it may be unnecessary for thetheranostic load to be detached from the nanoparticle for thetherapeutic or diagnostic effect to be achieved. For example, thetheranostic load may be bio-active even while attached to thenanoparticle. In element 530 of the method, the target region may beobserved. Observation of the target region may include imaging of thetarget region. Imaging may include detecting a dye included in thetheranostic loaded particle or interaction of the nanoparticle and/ortheranostic load with electromagnetic radiation.

The descriptions of the various embodiments of the present inventionhave been presented for purposes of illustration, but are not intendedto be exhaustive or limited to the embodiments disclosed. Manymodifications and variations will be apparent to those of ordinary skillin the art without departing from the scope and spirit of the describedembodiments. The terminology used herein was chosen to best explain theprinciples of the embodiments, the practical application or technicalimprovement over technologies found in the marketplace, or to enableothers of ordinary skill in the art to understand the embodimentsdisclosed herein.

While the foregoing is directed to embodiments of the present invention,other and further embodiments of the invention may be devised withoutdeparting from the basic scope thereof, and the scope thereof isdetermined by the claims that follow.

1. A material, comprising: a nanomaterial; and a polythioaminal having astructure:

wherein each R¹ is independently an organic or hetero-organic species,each R² is independently a substituent having a molecular weight no morethan 120 Daltons, X is a sulfur bonded species, Z is a linkage to thenanomaterial, and n is an integer greater than or equal to
 1. 2. Thematerial of claim 1, wherein X comprises a theranostic compound.
 3. Thematerial of claim 2, wherein the theranostic compound includes a dyemolecule.
 4. The material of claim 2, wherein the theranostic compoundincludes a biologically active species.
 5. The material of claim 2,wherein the theranostic compound is a therapeutic agent.
 6. The materialof claim 1, wherein the nanomaterial is a nanoparticle.
 7. The materialof claim 1, wherein the nanomaterial is a metal nanoparticle.
 8. Thematerial of claim 1, wherein at least one instance of R¹ includes apolyethylene glycol.
 9. The material of claim 1, wherein Z includes atleast one carbon atom.
 10. The material of claim 9, wherein Z is an-hexyl group.
 11. The material of claim 1, wherein the nanomaterial isa gold nanoparticle, at least one R¹ comprises a polyethylene glycol, R²is a methyl group, Z includes at least one carbon atom, and X comprisesa therapeutic compound.
 12. A method, comprising: functionalizing ananomaterial to provide a thiol end group connected thereto; exposingthe functionalized nanomaterial to a polythioaminal such that thepolythioaminal becomes linked to nanomaterial via the thiol end group,the polythioaminal having a general structure:

wherein each R¹ is independently an organic or hetero-organic species,each R² is independently a substituent having a molecular weight no morethan 120 Daltons, and n is an integer greater than or equal to
 1. 13.The method of claim 12, further comprising: exposing the nanomaterialhaving the polythioaminal linked thereto to a thiol compound having ageneral structure:HS—X wherein X is a species including at least one carbon atom.
 14. Themethod of claim 13, wherein X includes at least one of an alkyl group,an aromatic group, a peptide, or a nucleotide.
 15. The method of claim13, wherein X includes a theranostic compound.
 16. The method of claim15, wherein the theranostic compound is a therapeutic compound.
 17. Themethod of claim 12, wherein functionalizing the nanomaterial comprisesexposing the nanomaterial to a dithiol.
 18. The method of claim 17,wherein the nanomaterial is a gold nanoparticle, at least one instanceof R¹ includes a polyethylene glycol, and X includes a theranosticcompound.
 19. A method, comprising: supplying a nanomaterial to a targetregion of a biological sample, the nanomaterial having a theranosticcompound linked thereto via a polythioaminal having a structure:

wherein each R¹ is independently an organic or hetero-organic species,each R² is independently a substituent having a molecular weight no morethan 120 Daltons, X is the theranostic compound or a linkage thereto, Zis a linkage to the nanomaterial, and n is an integer greater than orequal to
 1. 20. The method of claim 19, wherein the nanomaterial is ametal nanoparticle.